Basically substituted (1h,3h)-quinazoline-2-thion-4-one derivatives

ABSTRACT

The present invention relates to new pharmacologically valuable, basically substituted (1H,3H)-quinazoline-2-thion-4-one derivatives having the structural formula WHEREIN R&#39;&#39; is a radical selected from the group consisting of N,Ndilower-alkylamino, N-lower alkyl-N-allyl-amino, N-lower alkylN-benzylamino, lower alkyl meaning alkyl having 1-4 carbon atoms; R1 is an alkoxy group having 1-4 carbon atoms attached to positions 6,7 or 6,7,8; R2 is an alkoxy group having 1-4 carbon atoms; M IS AN INTEGER SELECTED FROM THE GROUP CONSISTING OF 1,2 AND 3; N IS AN INTEGER SELECTED FROM THE GROUP CONSISTING OF 2 AND 3; OR THE PHARMACEUTICALLY ACCEPTABLE SALTS THEREOF, AND TO A PROCESS OF PRODUCING SAID DERIVATIVES BY ACETYLATING, OPTIONALLY IN THE PRESENCE OF AN ACID-BINDING AGENT, (1H,3H)quinazoline-2-thion-4-one derivatives having the structural formula WHEREIN R&#39;&#39;, R1 and n have the above-given meanings, with an alkoxy benzoic acid having the structural formula WHEREIN R2 and m have the meanings set out above, or a functional derivative thereof.

United States Patent [191 Beyerle et a1.

[451 Dec. 17, 1974 [75] Inventors: Rudi Beyerle, Bruchkobel,

5 Germany; Adolf Stachel, deceased,

late of Offenbach, Germany by lngeburg Lydia Katharina Stachel,executrix; Rolf-Eberhard Nitz, Bergen-Enkheim; Josef Scholtholt,Frankfurt-Fechenheim, both of Germany [73] Assignee: Cassella FarbwekeMainkur Aktiengesellschaft, Frankfurt, Germany 22 Filed: Apr. 17, 1973211 App]. No.: 351,830

Related U.S. Application Data [62] Division of Ser. No. 187,562, Oct. 7,1971,

Pat. NO. 3,455,223

[30] Foreign Application Priority Data Primary Examiner-Richard J.Gallagher Attorney, Agent, or FirmFrancis M. Crawford [57] ABSTRACT Thepresent invention relates to new pharmacologically valuable, basicallysubstituted (lH',3H)-quinazoline-2-thion-4-one derivatives having thestructural formula wherein R is a radical selected from the groupconsisting of N,N-dilower-alkylamino, N-lower alkyl-N-allyl-amino,N-lower alkyl-N-benzylamino, lower alkyl meaning alkyl having 1-4 carbonatoms; R is an alkoxy group having 1-4 carbon atoms attached topositions 6,7 or 6,7,8;

R is an alkoxy group having l-4 carbon atoms;

m is an integer selected from the group consisting of 1,2 and 3;

n is an integer selected from the group consisting of 2 and 3;

or the pharmaceutically acceptable salts thereof, and to a process ofproducing said derivatives by acetylating, optionally in the presence ofan acid-binding agent, lH,3H)-quinazoline-2-thion-4-one derivativeshaving the structural formula wherein R, R and n have the above-givenmeanings, with an alkoxy benzoic acid having the structural formulawherein R and m have the meanings set out above, or a functionalderivative thereof.

8 Claims, No Drawings BASICALLY SUBSTITUTED(lH,3H)-QUlNAZQLINE-2-THION-4-ONE DERIVATIVES The present application isa division of our US. pa-

tent application Ser. No 187,562, filed Oct. 7, 1971, now matured intoUS. Pat. No. 3,793,320.

The present invention relates to new pharmacologically valuable,basically substituted (ll-l,3l-l)-quinazo line-2-thion-4-one derivativeshaving the structural for- R is a radical selected from the groupconsisting of N.N-dilower-alkylamino, N-lower amino, N-loweralkyl-N-benzylamino, lower alkyl meaning alkyl having 1-4 carbon atoms;

R, is an alkoxy group having 1-4 carbon atoms attached to positions 6,7or 6,7,8;

R is an alkoxy group having l-4' carbon atoms;

m is an integer selected from the group consisting of 1,2 and 3; v

n is an integer selected from the group consisting of 2 and 3; or thepharmaceutically acceptable salts thereof and to a process of producingsaid derivatives by acetylating, optionally in the presence of anacid-binding agent, (1H,3H)-quinazoline-2- thion-4-one derivativeshaving the structural for- R, R, and n have the above-given meanings,with an alkoxy benzoic acid having the structural formula alkyl-N-allyl-0 hydrochlorides:

l. (R2)m wherein R and m have the meanings set out above, or afunctional derivative thereof.

The quinazoline-2-thion-4-ones required as starting material areprepared analogously to the description given in the Journal Helvet'iaChimica Acta 50 (1967), 1,440, by reacting the correspondinglysubstituted o-alkoxycarbonyl-phenylisothiocyanates with B-y-amino-B-hydroxypropylamines.

The 1l-l,3l-l )-quinazoline-2-thion-4-one derivatives 5 according to thepresent invention are valuable pharmaceuticals. In particular, they areexcellent coronary dilators and, in this respect, superior to otherknown substances of this kind.

With respect to the change in the oxygen tension in 20 the coronaryveinous blood, the pharmacological investigation of the vasodilatoraction on the coronary vessels was carried out in dogs according to'themethods described by W. K. A. Schaper and his co-workers (see. W. K. A.Schaper, R. Xhonneux, and J. M. Bogaard Uber die kontinuierliche Messungdes Sauerstoffdruckes im venosen Coronarblut" (Naunyn SchmiedebergsArch. exp. Path. u. Pharmak. 245, 383-389 (1963) The test preparationswere applied intravenously to the narcotized and spontaneously breathinganimals. On these tests conditions the dilasured according topolarographic methods by means of a platin electrode of theGleichmann-Lubbers type (see U. Gleichmann and D. W. Luebbers DieMessung des Sauerstoffdruckes in Gasen und Flussigkeiten mit derPlatin-Elektrode under besonderer Berucksichtigung der Messung im Blut,Pflu'gers Arch. 271, 431455 (1960) The heart ratewas continuouslymeasured by electronic methods from systolic peaks of the arterial bloodpressure. The arterial blood pressure was measured in the known mannerin the femoral artery with the aid of an electromanometer of theStaham-straingauge type.

The following table gives the results of the pharmacologicalinvestigations which were carried through. The preparations were testedin the form of their respective Maximal Change Preparatior LD .DosageMaximal increase Maximal Change in the Blood g./kg. mgJkg. in Oxy enTension in the Heart Pressure Mouse i.v. in the oronary Rate (systolic/i.v. Veinous Blood diastolic) in in Minutes in in Minutes in in Minutes3-1'y-dicthylamino-B-(3,4.5- trimcthoxybenzoxylrtipyll- 0.05 +77 30 1620 -7/l4' 2 o,7,8-trimcthoxy-( ll-Efi quinazoline-2-thion-4-onc3(y-di-n-propylamino-B- (3,4.5-trimethoxybcnzoxy)- prtl pyl]-6.7,8-trimethoxy- 0.05 46 50 25 l0 -5/i0 30 l ,3H)-quinazoline- I2-thion-4-one 3-( X-N-methyl-N-all lumino- 1H. .4.5-trimethoxy nzoxy)-pal ry] ]-6.7.8-trimethoxyl .3H)-quinazolinc-2-thion- 4-onc3-1y-N-methyl-N-bcnzylamino- Continued L980 g 1%- Mouse PreparatiorDosage Maximal increase in Oxy cn Tension in the i.v. Veinous BloodMaximal Change in the Heart oronary te in Minutes in Minutes ,B-( 3,4,S-trimethoxybenzoxy 0.05 proyl]-6.7.8-trimethoxyl1R3H)-quinazoline-Z-thion- 4-one3-1y-N-ethyl-N-cyclohcxylamino-[H 3.4.5-trimcthoxybenzoxy )-propyl ]-67,8- trimethoxy-( 1H,3H )-quinazolinc-2-thion-4-one3-[7-pyrrolidino-B-l3.4.5- trimethoxybenzoxy )lfltigfl6,7,8-trimethoxy-(l ,3 quinazoline-2-thion-4 one 3-[y-piperidin0-B-(3.4.5- trimethoxybenzoxy)nmlpyll- 0.1 6,7,8-trimethoxy-(l ,3

uinazoline-2-thion-4-one -['y-m0rpholino-B-(3,4.5- trimcthoxybenzoxy)flaro y1]- 6,7,8-trimethoxy-(l .3 quinazoline-2-thion-4-one 3-[7-N"(3,4-dimethoxybenzyl)-pi'perazino -8- (3.4,5-trimethoxybenzoxyprim!]-6.7.8-trimethoxyl H)-quinazoline-2-thion- B N hl h l --y-( '-p-corop enypiperazino)-B-( 3.4.5- trimcthoxybenzoxy )I-frwyl 1.06,7.8-trimethoxy-(1 ,3

uinazoline-2-thion-4-one -[y-diethylamino-B- (3.4.5-trimcthox bcnzoxy)-propyll- 0.069 0.1 5 6.7-dimethoxy-(1H3H)- quinazoline-Z-thion- 4 one3-[ -morpholinol3- 3,4,5-ll';melh01]t cnzoxy -propy 6,7-dimethoxy-(1H.3H)- quinazoline-Z-thiom 4-one3-[y-hexamethyleneimino-B-(3,4,5-trimethoxybenzoxy)- pro yl]-6,7,8-trimeoxy-(lH,3l-l)- quinazoline-2-thion- 4-one In the preparation of drageesand tablets containing as essential active ingredient the quinazolinederivatives of our invention these substances may be admixed with theconventional solid tabletting adjuvants, such as starch, lactose, talcand the like. Any of the tabletting materials and carriers customary inpharmaceutical practice may be employed.

For the preparation of the injection solutions the hydrochlorides of thequinazoline derivates are particularly suited since they have mostly agood watersolubility. injection solutions of water-insoluble productsmay of course be prepared in the conventional manner by concurrentlyusing well known suspending agents, emulsifiers and/or solubilizers.

For a better understanding of the natureand the 0bline-2-thion-4-one aredissolved in 250 c.c. chloroform and admixed with 11.1 g. (0.11 mol)triethylamine. Subsequently, while stirring at room temperature, asolution consisting of 25.3 g. (0.11 mol) 3,4,5- trimethoxybenzoylchloride in 80 c.c. chloroform is added dropwise during 30 minutes andstirring is continued for one hour at room temperature. The reactionmixture is heated to the boil and stirred for 6 hours under reflux.After cooling down it is evaporated to dryness in vacuo. The residue isdissolved with stirring in dilute hydrochloric acid and the thuslyobtained sojects of this invention, reference should be made to theethyl acetate. After drying Over Potassium Carbonate.

accompanying example which is of an illustrative rather than a limitingnature. Unless otherwise stated,

all temperatures given are in degrees Centigrade.

EXAMPLE 39.7 g. (011 mol) 3-( 'y-diethylamino-B-hydroxypropyl)-6,7,8-trimethoxy-( lH,3H)-quinazo-1H,3H)-quinazoline-2-thion-4-one in the form of colorless needlesmelting at 154 156. Yield: 43 g. (=68.5 percent-of the theoretical).

The 3-('y-diethylamino-B-hydroxypropyl)-6,7,8- MR trimethoxy-(lH,3H)-quinazoline-B-thion-4-one re- (RI)n 11- quired as startingmaterial may be prepared as follows: J-(OCHm 1))-= 165-107 28.3 .g. (0.1mol) 2,3,4-trimethoxy-6- (ii-(001mg: 3methoxycarbonyl-phenylisothiocyanate, prepared by 5 reacting analogouslyto the description given in Jourqua- 001ml N(n-C II )Q 153 455 nal ofOrganic Chemistry 27 (1962), 3,702 the methgggggggggg :gggfiggfiggmg vgm yl-3 ,4,5-trimethoxy anthranilate with thiophosgene, are 6,7,8(0CH3)3 mm dissolved in 200 c.c. anhydrous diethyl ether and, while *Nstlrrmg at room temperature, admixed with a solution 1Q 67,8 (OCH3)3 190consitmg of l4.6 g. (0.1 mol) -y-diethylammo-B- -N hydroxypropylamine in60 c.c. anhydrous diethylether. 7 OCH L Stirring is continued for 2hours at room temperature, 1897191 subsequently, the reaction productwhich separates in the form of crystals is sucked off and obtained isthe 3-. b I 173 (-y-diethy]amino-B-hydroxypropyl)-6,7,8-trimethoxy(ll-l,3l-l)-quinazoline2-thion-4-one in the form of colm mm 157-159oi-less needles, melting at 146.

Yield: 33 g. 83 percent of the theoretical) Analogously to the aboveprocess the following start- Gym (0033): 21mm mg materials may beprepared: N 01 General formula:

, r 7 1 '(0CHa)a N/\| 172 0 R, 25 Analogously to.the descr1pt1on givenin para 1 of tISIlS I 0H ;example, the following compounds of thepresent in- N vention are prepared'from the above starting materials: HGeneral formula:

\NCH1CH-CH2R (R011 I =5 I N 00 H 1 gag. (R1) 11 R chln r id e)ass-(00111 CH1); N ZHE Z 3,4,5 0oH, 3 6,7-(0 CH3): 156

3,4,5-(0CH9i 6,7.8-(0 c1193 N(nC3H1)2 I 119 a.4,s o CH3); 6,7,8-.(0CH1); -N(OH3) CH2CH=CH; 1 7s 3,4,5-(0 CH3); 6,7,8-(0 CH3) 3 N (CH3)CHzCeHs 130 3,4,5-(001193 ans- 0cm); 179

--N(C2H5) H 3, 1,5 0 CH1); 6,7,8-(0 CH1): l I 156-160 3,4, 5- (O 0113):;6,7,3(O CH3): 203

' L ans- 0cm 6,7,8-(00111); 138-140 ans- 0cm 6,7,8-(0 0113):, e011 260 N4 N CH OCH;

- -N N -o1 3): 163

1 Decomposed.

What is claimed is: 1. Basically substituted lH,3H)-quinazoline-2-thion-4-one derivatives having the structural formula wherein R is aradical selected from the group consisting of N,N-dilower-alkylamino,N-lower alkyl-N-allylamino, and N-lower alkyl-N-benzylamino, lower 8 2and 3; or the pharmaceutically acceptable salts thereof.

2. A compound according to claim 1, wherein R is a methoxy group.

3. A compound according to claim 1, wherein R is a methoxy group.

4. 3['y-Diethylamino-B-(3,4,5-trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy-( lH,3H)-quinazoline-2- thion-4-one, or thepharmaceutically acceptable salts thereof.

5. 3-['y-Di-n-propylamino-B-(3,4,5- trimethoxybenzoxy )-propyl]-6,7,8-trimethoxy- (lH,3H)-quinazoline-2-thion-4-one, or thepharmaceutically acceptable salts thereof.

6. 3-[y-N-methyl-N-allylamino-B-(3,4,5-trimethoxybenzoxy)-propyl]-6,7,8-trimethoxy-(lH,3H)-quinazoline-2-thion-4-one, or the pharmaceutically acceptablesalts thereof.

7. 3-['y-N-methyl-N-benzylamino-B-(3,4,5-trimethoxybenzoxy)-propyl]6,7,8-trimethoxy-(lH,3H)-quinazoline-2-thion-4-one, or the pharmaceutically acceptablesalts thereof.

8.- 3-[y-Diethylamino-B-(3,4,5-trimethoxybenzoxy)-propyl]-6,7-dimethoxy-( lH,3H)-quinazoline-2-thion- 4-one, or thepharmaceutically acceptable salts

1. BASICALLY SUBSTITUTED (1H,3H)-QUINAZOLINE-2-THION-4-ONE DERIVATIVESHAVING THE STRUCTURAL FORMULA
 2. A compound according to claim 1,wherein R1 is a methoxy group.
 3. A compound according to claim 1,wherein R2 is a methoxy group.
 4. 3( gamma -Diethylamino- Beta-(3,4,5-trimethoxybenzoxy)-propyl)-6,7,8-trimethoxy-(1H,3H)-quinazoline-2-thion-4-one, or the pharmaceutically acceptable salts thereof.
 5. 3-(gamma -Di-n-propylamino- Beta-(3,4,5-trimethoxybenzoxy)-propyl)-6,7,8-trimethoxy-(1H,3H)-quinazoline-2-thion-4-one, or the pharmaceutically acceptable salts thereof.
 6. 3-(gamma -N-methyl-N-allylamino- Beta-(3,4,5-trimethoxybenzoxy)-propyl)-6,7,8-trimethoxy-(1H,3H)-quinazoline-2-thion-4-one, or the pharmaceutically acceptable salts thereof.
 7. 3-(gamma -N-methyl-N-benzylamino- Beta-(3,4,5-trimethoxybenzoxy)-propyl)-6,7,8-trimethoxy-(1H,3H)-quinazoline-2-thion-4-one, or the pharmaceutically acceptable salts thereof.
 8. 3-(gamma -Diethylamino- Beta-(3,4,5-trimethoxybenzoxy)-propyl)-6,7-dimethoxy-(1H,3H)-quinazoline-2-thion-4-one,or the pharmaceutically acceptable salts thereof.